A Multicenter, Open-Label, Single-Arm, Prospective Clinical Study of PD-1 Inhibitor Combined With Rituximab, Methotrexate, and Orelabrutinib (PD-1i+RMO) in the Treatment of Newly Diagnosed Primary Central Nervous System Lymphoma (ND-PCNSL) and Secondary Central Nervous System Lymphoma (SCNSL)
Overview
- Phase
- Phase 2
- Status
- Recruiting
- Enrollment
- 50
- Locations
- 1
- Primary Endpoint
- 1 year Progression free survival (PFS)
Overview
Brief Summary
This is a multicenter, open-label, single-arm, prospective clinical study of PD-1 inhibitor combined with rituximab, methotrexate, and orelabrutinib (PD-1i+RMO) in the treatment of newly diagnosed primary central nervous system lymphoma (ND-PCNSL) and secondary central nervous system lymphoma (SCNSL). The primary endpoint is 1-year progression-free survival (PFS).
Detailed Description
Primary central nervous system lymphoma (PCNSL) is a B-cell non-Hodgkin lymphoma confined to the brain, spinal cord, cerebrospinal fluid, and/or eyes, with no evidence of systemic involvement. Patients with PCNSL have a poor prognosis, with a median survival of only 1-2 years. High-dose methotrexate (HD-MTX, >3 g/m² body surface area) remains the cornerstone of induction therapy and is often combined with other blood-brain barrier-penetrating agents, such as cytarabine or temozolomide. Recently, the addition of Bruton's tyrosine kinase (BTK) inhibitors to induction chemotherapy has been shown to significantly improve both the overall response rate (ORR) and complete response rate (CRR) in newly diagnosed patients.
To further enhance the complete response rate in patients with newly diagnosed PCNSL (ND-PCNSL) and secondary central nervous system lymphoma (SCNSL), sustain long-term remission, and improve progression-free survival (PFS) and overall survival (OS) after consolidation and maintenance therapy, this study will conduct a multicenter, open-label, prospective, single-arm clinical trial entitled: "PD-1 Inhibitor Combined with Rituximab, Methotrexate, and Orelabrutinib (PD-1i+RMO) for Newly Diagnosed PCNSL and SCNSL." The trial aims to evaluate the efficacy and safety of this combination regimen.
The PD-1i+RMO regimen is administered in 3-week cycles. After 4 cycles, disease assessment includes cranial MRI (non-contrast + contrast) and whole-body contrast-enhanced CT or PET/CT. Patients initially diagnosed via ophthalmologic examination will also undergo ophthalmic evaluation. Those with stable disease (SD) or progressive disease (PD) will discontinue the study, whereas patients achieving partial response (PR) or complete response (CR) will receive 4 additional cycles.
After completing all 8 cycles, cranial MRI (non-contrast + contrast) and PET/CT are repeated, with ophthalmologic follow-up if indicated. Patients with PR, SD, or PD after 8 cycles will exit the study. Those achieving CR will be evaluated by the investigators for autologous stem cell transplantation (ASCT) or whole-brain radiotherapy (WBRT), followed by a 2-year maintenance phase consisting of PD-1 inhibitor administered every 2 months in combination with orelabrutinib.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •\[1\] Newly diagnosed PCNSL confirmed by histopathology, or independently relapsed SCNSL (diffuse large B-cell lymphoma), diagnosed according to the 2016 WHO diagnostic criteria.
- •\[2\] Signed written informed consent, and ability to comply with protocol-specified visits and related procedures.
- •\[3\] Cranial MRI (non-contrast + contrast) performed within 28 days prior to study enrollment must show at least one measurable lesion in two perpendicular dimensions (according to the 2014 Lugano criteria).
- •\[4\] ECOG performance status of 0-
- •\[5\] Adequate organ and bone marrow function, defined as follows:
- •Hematology: Absolute neutrophil count (ANC) ≥ 1.0×10⁹/L, platelet count (PLT) ≥ 50×10⁹/L, hemoglobin (HGB) ≥ 8.0 g/dL; no administration of granulocyte growth factors, platelet transfusion, or red blood cell transfusion within 7 days prior to testing.
- •Liver function: Serum total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN.
- •Renal function: Serum creatinine (Cr) ≤ 1 × ULN or creatinine clearance (CCr) ≥ 90 mL/min.
- •Cardiac function: Cardiac function class below Grade III (NYHA criteria); echocardiography shows left ventricular ejection fraction (LVEF) ≥ 50%.
- •Coagulation: International normalized ratio (INR) ≤ 1.5 × ULN, activated partial thromboplastin time (APTT) ≤ ULN + 10 s, and prothrombin time (PT) ≤ ULN + 3 s.
Exclusion Criteria
- •Presence of disease involvement outside the central nervous system.
- •History of a second primary malignancy (except for adequately treated non-melanoma skin cancer, superficial bladder cancer, carcinoma in situ of the cervix, intramucosal carcinoma of the gastrointestinal tract, or breast carcinoma that has been cured and has shown no recurrence within the past 5 years).
- •History of allergic disease, severe drug allergy, or known hypersensitivity to macromolecular protein preparations or any component of the PD-1 monoclonal antibody injection formulation.
- •Prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibodies, or CAR-T cell therapy (or any other antibody targeting T-cell co-stimulation or checkpoint pathways).
- •Previous allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation.
- •Planned to receive other systemic anti-tumor therapies during the study period.
- •Use of anti-cancer vaccines or other immunostimulatory anti-tumor therapy within 3 months before the first dose.
- •Severe acute or chronic infection requiring systemic therapy.
- •Active, known, or suspected autoimmune disease (refer to Appendix 5), or history of such disease within the past 2 years (patients with vitiligo, psoriasis, alopecia, or Graves' disease not requiring systemic treatment in the past 2 years, hypothyroidism requiring only thyroid hormone replacement, or type 1 diabetes requiring only insulin replacement may be enrolled).
- •Use of immunosuppressive drugs within 4 weeks prior to the first study treatment, excluding intranasal, inhaled, or other local glucocorticoids or physiologic doses of systemic glucocorticoids (i.e., no more than 10 mg/day prednisone or equivalent).
Arms & Interventions
PD-1 Inhibitor Combined with Rituximab, Methotrexate, and Orelabrutinib (PD-1i+RMO)
Intervention: PD -1/PD-L1 monoclonal antibody (Drug)
PD-1 Inhibitor Combined with Rituximab, Methotrexate, and Orelabrutinib (PD-1i+RMO)
Intervention: Rituximab (R) (Drug)
PD-1 Inhibitor Combined with Rituximab, Methotrexate, and Orelabrutinib (PD-1i+RMO)
Intervention: Methotrexate (Drug)
PD-1 Inhibitor Combined with Rituximab, Methotrexate, and Orelabrutinib (PD-1i+RMO)
Intervention: Orelabrutinib (Drug)
PD-1 Inhibitor Combined with Rituximab, Methotrexate, and Orelabrutinib (PD-1i+RMO)
Intervention: ASCT/WBRT (Procedure)
Outcomes
Primary Outcomes
1 year Progression free survival (PFS)
Time Frame: From date of signing the informed consent until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 1 year
PFS is defined as the time from registration to the first occurrence of progression or relapse as assessed by the investigator, or death from any cause. PFS for patients without disease progression, relapse, or death will be censored at the time of the last tumor assessment.
Secondary Outcomes
- 1 year overall survival (OS)(From date of signing the informed consent until the date of death from any cause, whichever came first, assessed up to 1 year)
- Overall response rate (ORR)(At the end of induction therapy)
- Adverse Events(1 year)